Original Articles
Vol. 1 No. 3 (2022)
Pleiotropic effects of anti-thrombotic therapies: have direct oral anticoagulants any anti-inflammatory effect?
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Received: 16 August 2022
Accepted: 28 November 2022
Accepted: 28 November 2022
1218
Views
402
Downloads
Authors
Direct oral anticoagulants (DOACs) are currently recommended by European guidelines as the first line therapy for both stroke prevention in patients with atrial fibrillation (AF) and the prevention and the treatment of venous thromboembolism (VTE). Recently, it has been speculated that DOACs have anti-inflammatory capabilities in reducing the abnormal release of pro-inflammatory factors in addition to inhibiting the activation of factor X or factor II of the coagulation cascade. However, this hypothesis is based on limited pathophysiological data with small sample size, often on in vitro studies. Real-world, in vivo, and large clinical data are scarce. The aim of the present study was the evaluation of the possible anti-inflammatory and anti-proliferative effects of DOACs treatment in a cohort of patients affected by AF or VTE, by analyzing an extensive panel of cytokines and molecules involved in the process of vascular and tissue remodeling. Our data evidenced that DOACs treatment is associated with variations in systemic inflammation markers and in metalloproteinases. Further studies with larger number of patients are required to confirm these data.
Downloads
Download data is not yet available.
Citations
Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021;42:373-498. DOI: https://doi.org/10.1093/eurheartj/ehaa945
Konstantinides SV, Meyer G, Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020;41:543-603. DOI: https://doi.org/10.1093/eurheartj/ehz405
Nakamura M, Yamada N, Ito M. Novel Anticoagulant Therapy of Venous Thromboembolism:
Current Status and Future Directions. Ann Vasc Dis 2017;10:92-8. DOI: https://doi.org/10.3400/avd.ra.17-00015
Zirlik A, Bode C. Vitamin K antagonists: relative strengths and weaknesses vs. direct oral anticoagulants for stroke prevention in patients with atrial fibrillation. J Thromb Thrombolysis 2017;43:365-79. DOI: https://doi.org/10.1007/s11239-016-1446-0
Steffel J, Collins R, Antz M, et al. 2021 European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation. Europace 2021;23:1612-76. DOI: https://doi.org/10.1093/europace/euab157
Hu YF, Chen YJ, Lin YJ, Chen SA. Inflammation and the pathogenesis of atrial fibrillation. Nat Rev Cardiol 2015;12:230-43. DOI: https://doi.org/10.1038/nrcardio.2015.2
Hijazi Z, Aulin J, Andersson U, et al. Biomarkers of inflammation and risk of cardiovascular events in anticoagulated patients with atrial fibrillation. Heart 2016;102:508-17. DOI: https://doi.org/10.1136/heartjnl-2015-308887
Shbaklo H, Holcroft CA, Kahn SR. Levels of inflammatory markers and the development of the post-thrombotic syndrome. Thromb Haemost 2009;101:505-12. DOI: https://doi.org/10.1160/TH08-08-0511
Bittar LF, Silva LQD, Orsi FLA, et al. Increased inflammation and endothelial markers in patients with late severe post-thrombotic syndrome. PLoS One 2020;15:e0227150. DOI: https://doi.org/10.1371/journal.pone.0227150
Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med 2017;377:1119-31. DOI: https://doi.org/10.1056/NEJMoa1707914
Oesterle A, Laufs U, Liao JK. Pleiotropic Effects of Statins on the Cardiovascular System. Circ Res 2017;120:229-43. DOI: https://doi.org/10.1161/CIRCRESAHA.116.308537
Ren Y, Zhu H, Fan Z, et al. Comparison of the effect of rosuvastatin versus rosuvastatin/ezetimibe on markers of inflammation in patients with acute myocardial infarction. Exp Ther Med 2017;14:4942-50. DOI: https://doi.org/10.3892/etm.2017.5175
Mousavi S, Moradi M, Khorshidahmad T, Motamedi M. Anti-Inflammatory Effects of Heparin and Its Derivatives: A Systematic Review. Adv Pharmacol Sci 2015;2015:507151. DOI: https://doi.org/10.1155/2015/507151
Litov L, Petkov P, Rangelov M, et al. Molecular Mechanism of the Anti-Inflammatory Action of Heparin. Int J Mol Sci 2021;22:10730. DOI: https://doi.org/10.3390/ijms221910730
Basiak M, Kosowski M, Cyrnek M, et al. Pleiotropic Effects of PCSK-9 Inhibitors. Int J Mol Sci 2021;22:3144. DOI: https://doi.org/10.3390/ijms22063144
Spronk HM, de Jong AM, Crijns HJ, et al. Pleiotropic effects of factor Xa and thrombin: what to expect from novel anticoagulants. Cardiovasc Res 2014;101:344-51. DOI: https://doi.org/10.1093/cvr/cvt343
Bukowska A, Zacharias I, Weinert S, et al. Coagulation factor Xa induces an inflammatory signalling by activation of protease-activated receptors in human atrial tissue. Eur J Pharmacol 2013;718:114-23. DOI: https://doi.org/10.1016/j.ejphar.2013.09.006
Ruf W. Roles of factor Xa beyond coagulation. J Thromb Thrombolysis 2021;52:391-6. DOI: https://doi.org/10.1007/s11239-021-02458-8
Ten Cate H, Guzik TJ, Eikelboom J, Spronk HMH. Pleiotropic actions of factor Xa inhibition in cardiovascular prevention: mechanistic insights and implications for anti-thrombotic treatment. Cardiovasc Res 2021;117:2030-44. DOI: https://doi.org/10.1093/cvr/cvaa263
Al-Tamimi M, Grigoriadis G, Tran H, et al. Coagulation-induced shedding of platelet glycoprotein VI mediated by factor Xa. Blood 2011;117:3912-20. DOI: https://doi.org/10.1182/blood-2010-08-301523
Kondo H, Abe I, Fukui A, et al. Possible role of rivaroxaban in attenuating pressure-overload-induced atrial fibrosis and fibrillation. J Cardiol 2018;71:310-9. DOI: https://doi.org/10.1016/j.jjcc.2017.08.007
Matsuura T, Soeki T, Fukuda D, et al. Activated Factor X Signaling Pathway via ProteaseActivated Receptor 2 Is a Novel Therapeutic Target for Preventing Atrial Fibrillation. Circ J 2021;85:1383-91. DOI: https://doi.org/10.1253/circj.CJ-20-1006
Tsujino Y, Sakamoto T, Kinoshita K, et al. Edoxaban suppresses the progression of atrial fibrosis and atrial fibrillation in a canine congestive heart failure model. Heart Vessels 2019;34:1381-8. DOI: https://doi.org/10.1007/s00380-019-01377-2
Hara T, Fukuda D, Tanaka K, et al. Inhibition of activated factor X by rivaroxaban attenuates neointima formation after wire-mediated vascular injury. Eur J Pharmacol 2018;820:222-8. DOI: https://doi.org/10.1016/j.ejphar.2017.12.037
Amini S, Gholami K, Bakhshandeh H, Fariborz Farsad B. Effect of Oral Anticoagulant Therapy on Coagulation Activity and Inflammatory Markers in Patients with Atrial Fibrillation Undergoing Ablation: A Randomized Comparison between Dabigatran and Warfarin. Iran J Pharm Res 2013;12:945-53.
Katoh H, Nozue T, Michishita I. Anti-inflammatory effect of factor-Xa inhibitors in Japanese patients with atrial fibrillation. Heart Vessels 2017;32:1130-6. DOI: https://doi.org/10.1007/s00380-017-0962-y
Pignatelli P, Pastori D, Bartimoccia S, et al. Anti Xa oral anticoagulants inhibit in vivo platelet activation by modulating glycoprotein VI shedding. Pharmacol Res 2016;116:484-9. DOI: https://doi.org/10.1016/j.phrs.2016.09.035
Nakase T, Moroi J, Ishikawa T. Anti-inflammatory and antiplatelet effects of non-vitamin K antagonist oral anticoagulants in acute phase of ischemic stroke patients. Clin Transl Med 2018;7:2. DOI: https://doi.org/10.1186/s40169-017-0179-9
Zemer-Wassercug N, Haim M, Leshem-Lev D, et al. The effect of dabigatran and rivaroxaban on platelet reactivity and inflammatory markers. J Thromb Thrombolysis 2015;40:340-6. DOI: https://doi.org/10.1007/s11239-015-1245-z
Terry CM, He Y, Cheung AK. Rivaroxaban improves patency and decreases inflammation in a mouse model of catheter thrombosis. Thromb Res 2016;144:106-12. DOI: https://doi.org/10.1016/j.thromres.2016.06.008
Chan MY, Lin M, Lucas J, et al. Plasma proteomics of patients with non-valvular atrial fibrillation on chronic anticoagulation with warfarin or a direct factor Xa inhibitor. Thromb Haemost 2012;108:118091. DOI: https://doi.org/10.1160/TH12-05-0310
Li CY, Zhang JR, Hu WN, Li SN. Atrial fibrosis underlying atrial fibrillation (Review). Int J Mol Med 2021;47:9. DOI: https://doi.org/10.3892/ijmm.2020.4842
Xintarakou A, Tzeis S, Psarras S, et al. Atrial fibrosis as a dominant factor for the development of atrial fibrillation: facts and gaps. Europace 2020;22:342-51. DOI: https://doi.org/10.1093/europace/euaa009
Liu Y, Xu B, Wu N, et al. Association of MMPs and TIMPs With the Occurrence of Atrial Fibrillation: A Systematic Review and Metaanalysis. Can J Cardiol 2016;32:803-13. DOI: https://doi.org/10.1016/j.cjca.2015.08.001
Zhan G, Wenhua G, Jie H, et al. Potential roles of circulating matrix metalloproteinase-28 (MMP-28) in patients with atrial fibrillation. Life Sci 2018;204:15-9. DOI: https://doi.org/10.1016/j.lfs.2018.04.053
Mukherjee R, Akar JG, Wharton JM, et al. Plasma profiles of matrix metalloproteinases and tissue inhibitors of the metalloproteinases predict recurrence of atrial fibrillation following cardioversion. J Cardiovasc Transl Res 2013;6:528-35. DOI: https://doi.org/10.1007/s12265-013-9471-2
Wang W, Zhang HT, Yang XL. Effect of matrix metalloproteinase and their inhibitors on atrial myocardial structural remodeling. J Cardiovasc Med (Hagerstown) 2013;14:265-9. DOI: https://doi.org/10.2459/JCM.0b013e328354e458
Jia M, Li ZB, Li L, et al. Role of matrix metalloproteinase‑7 and apoptosis‑associated gene expression levels in the pathogenesis of atrial fibrosis in a Beagle dog model. Mol Med Rep 2017;16:6967-73. DOI: https://doi.org/10.3892/mmr.2017.7415
de Franciscis S, Gallelli L, Amato B, et al. Plasma MMP and TIMP evaluation in patients with deep venous thrombosis: could they have a predictive role in the development of post-thrombotic syndrome? Int Wound J 2016;13:1237-45. DOI: https://doi.org/10.1111/iwj.12489
Zhang T, Li Q, Wang L, Li G. Expression variations and clinical significance of MMP-1, MMP-2 and inflammatory factors in serum of patients with deep venous thrombosis of lower extremity. Exp Ther Med 2019;17:181-6. DOI: https://doi.org/10.3892/etm.2018.6922
Mosevoll KA, Johansen S, Wendelbo Ø, et al. Cytokines, Adhesion Molecules, and Matrix Metalloproteases as Predisposing, Diagnostic, and Prognostic Factors in Venous Thrombosis. Front Med (Lausanne) 2018;5:147. DOI: https://doi.org/10.3389/fmed.2018.00147
Saghazadeh A, Hafizi S, Rezaei N. Inflammation in venous thromboembolism: Cause or consequence? Int Immunopharmacol 2015;28:655-65. DOI: https://doi.org/10.1016/j.intimp.2015.07.044
Zhang YB, Li W, Yao LQ, et al. Expression changes and roles of matrix metalloproteinases in a rat model of traumatic deep vein thrombosis. Chin J Traumatol 2010;13:188-92.
How to Cite
1.
Gori AM, Camilleri E, Bertelli A, Rogolino A, Cesari F, Lotti E, et al. Pleiotropic effects of anti-thrombotic therapies: have direct oral anticoagulants any anti-inflammatory effect?. Bleeding Thromb Vascul Biol [Internet]. 2022 Dec. 14 [cited 2026 Jan. 25];1(3). Available from: https://www.btvb.org/btvb/article/view/50
Copyright (c) 2022 The Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Similar Articles
- Silvia Cardi, Filippo Catalani, Luca Valerio, Stefano Barco, From rare to aware: confronting Lemierre syndrome , Bleeding, Thrombosis and Vascular Biology: Vol. 3 No. 3 (2024)
- Matteo Guarascio, Gerardo Nicola Pititto, Alessia Abenante, Marco Paolo Donadini, Distal deep vein thrombosis: is there a way out of this dark forest? , Bleeding, Thrombosis and Vascular Biology: Vol. 3 No. 2 (2024)
- CS04 | Association between elevated plasma levels of tissue plasminogen activator and occult cancer risk: a nested case-cohort analysis in 10,294 healthy subjects , Bleeding, Thrombosis and Vascular Biology: Vol. 4 No. s1 (2025)
- Marialaura Bonaccio, Licia Iacoviello, Maria Benedetta Donati, It’s definitely time to consider diet in its ultra-processing form as a major risk factor for thrombotic vascular disorders , Bleeding, Thrombosis and Vascular Biology: Vol. 2 No. 3 (2023)
- Giuseppe Camporese, Paolo Prandoni, Walter Ageno, Aspirin or low-molecular weight heparin for thromboprophylaxis after a fracture? That is the question , Bleeding, Thrombosis and Vascular Biology: Vol. 2 No. 2 (2023)
- Marwa Eltemamy, Robert Namushi, Narayanamoorthi Saravanan, Importance of assessment of carotid plaques in the managementof acute ischemic stroke: floating intracarotid plaque , Bleeding, Thrombosis and Vascular Biology: Vol. 2 No. 3 (2023)
- CO16 | The predictive value of high-sensitivity C-reactive protein for assessing thrombosis risk in non-small cell lung cancer , Bleeding, Thrombosis and Vascular Biology: Vol. 4 No. s1 (2025)
- CO17 | Clinical relevance of isolated anti-phosphatidylserine/ prothrombin antibody positivity , Bleeding, Thrombosis and Vascular Biology: Vol. 4 No. s1 (2025)
- PO59 | Efficacy and safety of different anticoagulant treatment regimens for isolated internal jugular vein thrombosis: a case series , Bleeding, Thrombosis and Vascular Biology: Vol. 4 No. s1 (2025)
- Giovanni Tiscia, Elvira Grandone, Talking about assisted reproductive techniques and thromboembolic risk: everything we always wanted to know , Bleeding, Thrombosis and Vascular Biology: Vol. 1 No. 2 (2022)
You may also start an advanced similarity search for this article.
Most read articles by the same author(s)
- Daniela Poli, Walter Ageno, Emilia Antonucci, Salvatore Bradamante, Eugenio Bucherini, Paolo Chiarugi, Antonio Chistolini, Benilde Cosmi, Anna Falanga, Antonio Insana, Domenico Lione, Rosa Maria Lombardi, Giuseppe Malcangi, Rossella Marcucci, Giuliana Martini, Lucilla Masciocco, Carmelo Paparo, Daniele Pastori, Simona Pedrini, Vittorio Pengo, Pasquale Pignatelli, Andrea Toma, Sophie Testa, Gualtiero Palareti, Management of anticoagulation in atrial fibrillation patients in Italy: insight from the Atrial Fibrillation-Survey on Anticoagulated Patients Register (AF-START) , Bleeding, Thrombosis and Vascular Biology: Vol. 2 No. 2 (2023)
- Martina Berteotti, Walter Ageno, Rossella Marcucci, Andrea Stella, Paolo Zamboni, Romeo Martini, The role of dyslipidemia and gender-related risk factors in the management of patients with abdominal aortic aneurysms: a survey from the Italian Society of Angiology and Vascular Medicine and a call to action , Bleeding, Thrombosis and Vascular Biology: Vol. 4 No. 2 (2025)
- Rossella Marcucci, Rosanna Abbate, What is the gender of thrombosis? A natural model of precision medicine , Bleeding, Thrombosis and Vascular Biology: Vol. 2 No. 3 (2023)
- Eleonora Petito, Anna Maria Mezzasoma, Emanuela Falcinelli, Chiara Conti, Erica De Candia, Raimondo De Cristofaro, Silvia Sorrentino, Gian Marco Podda, Mariangela Scavone, Anna Falanga, Marina Marchetti, Luca Barcella, Stefania Basili, Lucia Stefanini, Andrea Boccatonda, Laura Contino, Patrizia Sciancalepore, Igor Florio, Egidio Imbalzano, Rossella Marcucci, Angela Rogolino, Patrizia Noris, Marta Panella, Rita Santoro, Maria Costanza Turi, Gaetano Vaudo, Rosa Curcio, Paolo Gresele, Persistence of functional anti-PF4 antibodies and neutrophil activation in vaccine-induced immune thrombotic thrombocytopenia , Bleeding, Thrombosis and Vascular Biology: Vol. 4 No. 3 (2025)
